Blueprint Medicines' Highly Selective RET Inhibitor BLU-667 Shows Durable Anti-Tumor Activity in Patients with RET-Altered Cancers in Updated ARROW Trial Data Presented at ASCO 2019
-- Responses observed across treatment-naïve and previously treated patients, and regardless of RET alteration or tumor type --
-- Strong activity against brain metastases in NSCLC patients --
-- Plan to submit initial NDA to
The new results support
"Targeted therapies have transformed the management of multiple oncogenic subsets of lung cancer, but RET-fusion positive lung cancers have not derived similar benefit from current therapeutic approaches. To date, no selective RET inhibitors are approved," said
"This growing body of evidence supports our plans to rapidly advance BLU-667, a highly selective RET inhibitor, for the treatment of patients with RET-altered cancers," said
Highlights from ASCO Presentations of ARROW Trial Data
The presented data include 120 patients with RET-fusion NSCLC, 64 patients with RET-mutant MTC and 12 patients with other RET-altered cancers (nine papillary thyroid cancer (PTC), two pancreatic cancer and one intrahepatic bile duct carcinoma) enrolled in the ARROW trial as of a data cutoff date of
At baseline, 40 percent of the RET-fusion NSCLC patients had brain metastases. Brain metastases commonly occur in NSCLC patients, and the prognosis in these patients is typically poor. Regardless of starting dose and including the dose-escalation portion of the ARROW trial, the RET-fusion NSCLC patients have been on treatment up to 24 months.
For clinical activity data, NSCLC and MTC patients were evaluable if they were enrolled as of
Clinical Activity Data — RET-Fusion NSCLC
As of the data cutoff date, 48 patients with RET-fusion NSCLC were evaluable for response assessment, including 35 patients previously treated with platinum-based chemotherapy.
- Nearly all patients (90 percent) had radiographic tumor reductions.
- The objective response rate (
ORR) was 60 percent (one complete response and 20 partial responses (PR); all responses were confirmed), and the disease control rate1 (DCR) was 100 percent in the patients previously treated with platinum-based chemotherapy.
ORRwas 71 percent (five confirmed PRs) in seven patients naïve to prior systemic treatment.
- Across all patients, the median duration of response (DOR) was not reached, and 82 percent of responders remained on treatment as of the data cutoff date.
- In nine patients with measurable brain metastases, 78 percent had shrinkage of brain metastases.
- No patients starting at the 400 mg QD dose had disease progression due to new brain involvement.
- BLU-667 was highly active regardless of RET fusion partner, including RET-KIF5B and RET-CCDC6.
Clinical Activity Data — RET-Mutant MTC and Other RET-Altered Cancers
As of the data cutoff date, 32 patients with RET-mutant MTC were evaluable for response assessment, including 16 patients previously treated with the MKIs cabozantinib or vandetanib.
ORRwas 63 percent (nine confirmed PRs, one PR pending confirmation) and the DCR was 94 percent in RET-mutant MTC patients previously treated with cabozantinib or vandetanib.
- Across all RET-mutant MTC patients, the median DOR was not reached and all responders remained on treatment as of the data cutoff date, with treatment durations up to 15.6 months for patients receiving a starting dose of 400 mg QD.
As of the data cutoff date, clinical activity data were reported in patients with other RET-altered cancers:
- Six patients with PTC were evaluable for response assessment by RECIST version 1.1. In these patients, the
ORRwas 83 percent (three confirmed PRs, two PRs pending confirmation).
- Five patients with PTC have remained on treatment for one year or longer, and eight patients with PTC remained on treatment as of the data cutoff date.
- Additional responses were observed in patients with other RET-fusion cancers, including pancreatic cancer (one confirmed PR, one PR pending confirmation) and intrahepatic bile duct carcinoma (one confirmed PR).
Four patients (two with RET-fusion NSCLC, two with RET-mutant MTC) enrolled in the ARROW trial were previously treated with LOXO-292. Among them:
- Two patients had a PR, one of which was confirmed as of the data cutoff date, and one of which was pending as of the data cutoff date and subsequently confirmed prior to the presentation.
- One patient had stable disease with radiographic tumor reductions and remained on treatment as of the data cutoff date.
As of the data cutoff date, 226 patients received a starting dose of 400 mg QD and were evaluable for safety. Across all patients, BLU-667 was well-tolerated and most adverse events (AEs) reported by investigators were Grade 1 or 2. Across all grades, the most common treatment-emergent AEs (regardless of relationship to BLU-667) reported by investigators (≥15 percent) were constipation, hypertension, increased aspartate aminotransferase, neutropenia, diarrhea, fatigue, anemia, increased alanine aminotransferase and increased blood creatinine. Investigator-reported Grade 3 or 4 treatment-related AEs (≥2 percent) included neutropenia, hypertension, anemia, increased blood creatine phosphokinase and leukopenia.
Across all patients, only 4 percent of patients discontinued treatment with BLU-667 due to treatment-related AEs. Seven percent of patients with RET-fusion NSCLC discontinued treatment with BLU-667 due to treatment-related AEs, and no patients with RET-mutant MTC discontinued treatment with BLU-667 due to treatment-related AEs.
These updated data for BLU-667 were reported in two presentations at the
BLU-667 Clinical Development Update
Based on encouraging clinical activity in patients with NSCLC naïve to prior systemic therapy and feedback from the
Investor Event and Webcast Information
About the ARROW Trial
ARROW is a Phase 1 clinical trial designed to evaluate the safety, tolerability and efficacy of BLU-667 in multiple ascending doses in adults with RET-altered NSCLC, MTC and other advanced solid tumors. The trial consists of two parts: a dose escalation portion, which is now complete, and an expansion portion, in which enrollment is ongoing. The expansion portion consists of seven defined cohorts of patients treated with BLU-667 at the RP2D of 400 mg QD: (1) RET-fusion NSCLC patients previously treated with a platinum-based chemotherapy, (2) RET-fusion NSCLC patients who have not previously received a platinum-based chemotherapy, (3) RET-mutant MTC patients previously treated with cabozantinib or vandetanib, (4) RET-mutant MTC patients who have not previously received cabozantinib or vandetanib, (5) patients with other RET-fusion tumors, (6) patients with other RET-mutant tumors and (7) RET-altered solid tumor patients previously treated with a selective RET inhibitor. Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety. The trial is enrolling patients at multiple sites in
Patients and physicians interested in the ARROW clinical trial can contact the
About RET-Altered Solid Tumors
RET activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and MTC. RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC and approximately 10 to 20 percent of patients with PTC, while RET mutations are implicated in approximately 90 percent of patients with advanced MTC. In addition, oncogenic RET alterations are observed at low frequencies in colorectal, breast, pancreatic and other cancers, and RET fusions have been observed in patients with treatment-resistant, EGFR-mutant NSCLC.
Currently, there are no approved therapies that selectively target RET-driven cancers, although there are several approved MKIs with RET activity being evaluated in clinical trials. To date, clinical activity attributable to RET inhibition has been uncertain for these approved MKIs, likely due to insufficient inhibition of RET and off-target toxicities. There is a need for precision therapies that provide durable clinical benefit by selectively targeting RET alterations and anticipated resistance mutations.
BLU-667 is an investigational, once-daily oral precision therapy specifically designed for highly potent and selective targeting of oncogenic RET alterations.
BLU-667 was designed by
Blueprint Medicines is a precision therapy company striving to improve human health. With a focus on genomically defined cancers, rare diseases and cancer immunotherapy, we are developing transformational medicines rooted in our leading expertise in protein kinases, which are proven drivers of disease. Our uniquely targeted, scalable approach empowers the rapid design and development of new treatments and increases the likelihood of clinical success. We are currently advancing four investigational medicines in clinical development, along with multiple research programs. For more information, visit www.BlueprintMedicines.com and follow us on Twitter (@BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans and timelines for the clinical development of BLU-667; expectations regarding the potential benefits of BLU-667 in treating patients with RET-fusion NSCLC, RET-mutant MTC and other RET-altered cancers; plans and timelines for submitting an NDA to the
1 Defined as the rate of complete responses, PRs and stable disease in patients evaluable for response assessment.
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